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Future Considerations in Nocturia and Nocturnal Polyuria

Open AccessPublished:June 21, 2019DOI:https://doi.org/10.1016/j.urology.2019.06.014

      Abstract

      Nocturnal polyuria (NP), the most common etiology of nocturia, can be caused by various medical conditions, including cardiovascular disease, obstructive sleep apnea, renal tubular dysfunction, as well as medications (eg, diuretics) and/or behavioral patterns. NP in the absence of underlying medical conditions has been described as NP syndrome and is thought be the result of impaired circadian release of endogenous arginine vasopressin. Desmopressin, a synthetic arginine vasopressin analog, has been shown to be an effective replacement therapy in adults with nocturia due to NP. Further studies on the subset of patients with NP syndrome are warranted to maximize benefit from antidiuretic treatment. In addition, a connection between the pathophysiological mechanisms underlying NP and essential hypertension has been suggested, and hypertension has been shown to be a significant risk factor for nocturia, while an association between NP and brain natriuretic peptide levels has also been reported in patients with nocturia. Hypertension is now viewed as a disorder of blood vessels and treatment is directed at the vasculature rather than the blood pressure, with the latter currently serving as a biomarker for arterial injury. Nocturia is thought to be associated with the beginning of this cardiovascular continuum as studies have reported a link between coronary heart disease and nocturia. Therefore, there is an increasing need to elucidate the complex mechanisms implicated in the association between nocturia and hypertension to promote the development of more individualized therapies for the treatment of nocturia.
      Nocturnal polyuria (NP), which is characterized by overproduction of urine at night, can be caused by various medical conditions (both clinical and subclinical), including cardiovascular disease, obstructive sleep apnea (OSA), excessive fluid intake, renal tubular dysfunction, as well as the use of medications such as diuretics, and/or modifiable behavioral factors (ie, excessive evening fluid intake).
      • Cornu J-N
      • Abrams P
      • Chapple CR
      • et al.
      A contemporary assessment of nocturia: definition, epidemiology, pathophysiology, and management—a systematic review and meta-analysis.
      NP may also result from abnormalities in normal circadian variation in endogenous arginine vasopressin (AVP) secretion.
      • Weiss JP.
      Nocturia: focus on etiology and consequences.
      NP in the absence of identifiable causes is known as NP syndrome (NPS) and is thought to be due to impaired circadian release of AVP,
      • Asplund R.
      The nocturnal polyuria syndrome (NPS).
      which plays a key role in the control of urine production by increasing water absorption and concentration of urine at night.
      • Weiss JP.
      Nocturia: focus on etiology and consequences.
      Desmopressin acetate, a synthetic analog of AVP, is a selective vasopressin receptor 2 agonist that induces antidiuresis and has been shown to be an effective replacement therapy for adults with nocturia due to NP.
      • Weiss JP
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      Management of nocturia: the role of antidiuretic pharmacotherapy.
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      • Zinner NR
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      Desmopressin orally disintegrating tablet effectively reduces nocturia: results of a randomized, double-blind, placebo-controlled trial.
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      • Group NS
      Efficacy of desmopressin (Minirin) in the treatment of nocturia: a double-blind placebo-controlled study in women.
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      Efficacy and safety of SER120 nasal spray in patients with nocturia: pooled analysis of 2 randomized, double-blind, placebo controlled, phase 3 trials.
      Further investigation into those patients who would most benefit from antidiuretic treatment is needed.
      Based on continued investigation and understanding of the underlying pathophysiological multifaceted mechanisms of nocturia and NP, it is becoming increasingly clear that there are several factors linking nocturia and NP with a broad range of systemic disorders, including hypertension, cardiovascular disease, type 2 diabetes mellitus (T2DM), and other metabolic disorders. Hypertension has been shown to be a significant risk factor (odds ratio [OR] 1.64) for nocturia,
      • Yoshimura K
      • Terada N
      • Matsui Y
      • Terai A
      • Kinukawa N
      • Arai Y
      Prevalence of and risk factors for nocturia: analysis of a health screening program.
      while an association between NP and brain natriuretic peptide (BNP) levels has also been reported in patients with nocturia.
      • Sone A
      • Kondo N
      • Kobayashi T
      • et al.
      Association with relative nocturnal polyuria using bnp (brain natriuretic peptide) in eldely patients with nocturia.
      Furthermore, with hypertension now viewed as a disorder of the blood vessels and blood pressure serving as a biomarker for arterial injury, the association between nocturia and arterial injury is also of interest. This review is the final in a series of articles published in this supplement that summarizes the presentations and discussions from a roundtable meeting focused on nocturia and NP. It summarizes new areas of investigation and future considerations for identification of patients with NP, for understanding the etiology, and for exploring the area of growing interest into the links between nocturia and hypertension, cardiovascular disease, and other conditions.

      NPS Prevalence and Characterization of NPS Based on Diuresis Rates

      Since NPS is defined as NP in the absence of identifiable contributory factors, it is important to understand the prevalence of NPS to optimize treatment management. The prevalence of NPS in patients seeking treatment for nocturia was studied by using voiding diaries to assess the percentage of patients with NP (the “upper limit”) and the percentage of patients with NP after excluding those with comorbidities and exogenous factors that could cause nocturia (“lower limit”).

      Emeruwa C, Epstein MR, Michelson KP, Monaghan T, Weiss JP. Prevalence of the nocturnal polyuria syndrome in the Veterans Affairs outpatient urology setting. Paper presented at: Annual Meeting of the Urological Society for American Veterans. May 5, 2019; Chicago, IL.

      Patients reporting less than 2 nocturnal voids were excluded, along with those with comorbidities associated with NP such as OSA, congestive heart failure (CHF), chronic kidney disease (CKD), peripheral edema, diabetes insipidus (DI), and uncontrolled diabetes mellitus. Patients on diuretics or those reporting excessive evening fluid intake were also excluded. As the study design precluded identification of patients with NP owing to nondipping nocturnal hypertension, patients with hypertension were initially included establishing a “ceiling prevalence” NPS, and then excluded to determine a “floor value.” A total of 283 diaries were completed, of which 202 were marked with ≥2 nocturnal voids. Using the NP index (NPi) >0.33 definition (nocturnal urine volume [NUV] >33% of total 24-hour urine volume),
      • Epstein M
      • Blaivas J
      • Wein AJ
      • Weiss JP
      Nocturia treatment outcomes: analysis of contributory frequency volume chart parameters.
      • van Kerrebroeck P
      • Abrams P
      • Chaikin D
      • et al.
      The standardisation of terminology in nocturia: report from the standardisation sub-committee of the International Continence Society.
      134 (66%) patients were identified with NP (“upper limit”). Excluding patients with DI, OSA, CHF, CKD, edema, and those on furosemide, 83 (41%) patients remained, of which 41 were hypertensive, resulting in 42 (21%) patients with NPS (“lower limit”). Using the nocturnal urine production (NUP) >90 mL/h definition, 103 (51%) patients were identified with NP (“upper limit”). Excluding patients with DI, OSA, CHF, CKD, edema, and those on furosemide, 65 (32%) patients remained, of which 31 were hypertensive, resulting in 34 (17%) patients with NPS (“lower limit”). Therefore, a total of 17%-21% of patients seeking treatment for nocturia, were thought to have NPS.

      Emeruwa C, Epstein MR, Michelson KP, Monaghan T, Weiss JP. Prevalence of the nocturnal polyuria syndrome in the Veterans Affairs outpatient urology setting. Paper presented at: Annual Meeting of the Urological Society for American Veterans. May 5, 2019; Chicago, IL.

      While NPS has been defined,
      • Asplund R.
      The nocturnal polyuria syndrome (NPS).
      it has not yet been fully characterized. Until recently, it was not understood whether loss of normal circadian oscillations in urine production in patients with NPS resulted in a uniformly high or phasic nocturnal diuresis rate (DR). To this end, changes in DR throughout the night between sleeping hours before and after the first nocturnal awakening to void were studied,
      • Monaghan TF
      • Suss NR
      • Epstein MR
      • et al.
      Differential nocturnal diuresis rates among patients with and without nocturnal polyuria syndrome.
      based on a voiding diary database of 773 entries from 440 adult men treated at a Veterans Affairs clinic for lower urinary tract symptoms (LUTS). Patients were excluded if they were taking diuretics or had OSA, CHF, edema, CKD, or DI. Analyses were performed using 2 different cut offs for NP: NUP >90 mL/h and NPi >0.33. After exclusions, a total of 130 individuals were included and divided into 2 cohorts: patients with NP and patients who were below the threshold for NP. Early nocturnal DR (ENDR; first nocturnal voided volume/length of first uninterrupted sleep period), late nocturnal DR (LNDR; remaining NUV/remaining hours of sleep), and diurnal DR (daytime urine volume/hours awake) were compared in patients with NPS.
      • Monaghan TF
      • Suss NR
      • Epstein MR
      • et al.
      Differential nocturnal diuresis rates among patients with and without nocturnal polyuria syndrome.
      Patients with NPS showed a significant decrease from ENDR to LNDR at NUP >90 mL/h (152 vs 120 mL/h, P = .02) and NPi >0.33 (120 vs 91 mL/h, P = .02), compared with patients without NPS who exhibited a uniform nocturnal DR (60 vs 59 mL/h, P = .29, and 75 vs 75 mL/h, P = .25, for the 2 definitions, respectively) (Fig. 1).
      • Monaghan TF
      • Suss NR
      • Epstein MR
      • et al.
      Differential nocturnal diuresis rates among patients with and without nocturnal polyuria syndrome.
      Figure 1
      Figure 1Nocturnal diuresis rate in patients with and without nocturnal polyuria syndrome based on the 2 nocturnal polyuria definitions. NPi, nocturnal polyuria index; NPS, nocturnal polyuria syndrome; NUP, nocturnal urine production. Reprinted from Monaghan et al.
      • Monaghan TF
      • Suss NR
      • Epstein MR
      • et al.
      Differential nocturnal diuresis rates among patients with and without nocturnal polyuria syndrome.
      Current formulations of antidiuretics have a short half-life, exerting their effect during the early hours of sleep. Therefore, the significant drop-off in nocturnal DR after the time of first awakening that is unique in patients with NPS and the large volume of urine produced in the early hours of sleep may provide a specific target for short-acting antidiuretics approved for use in patients with nocturia due to NPS.
      • Monaghan TF
      • Suss NR
      • Epstein MR
      • et al.
      Differential nocturnal diuresis rates among patients with and without nocturnal polyuria syndrome.
      The nocturnal DR was further investigated in patients with NPS or secondary NP.

      Epstein M, Monaghan T, Michelson K, et al. Nocturnal diuresis rate patterns in nocturnal polyuria syndrome and secondary nocturnal polyuria. Paper presented at: Annual Meeting of the American Urological Association. May 3-6, 2019; Chicago, IL.

      A database of voiding diaries from patients managed for nocturia, at a Veterans Affairs urology clinic from 2007 to 2018, was retrospectively analyzed. Patients were divided into 5 etiologies for NP; namely, NPS, DI, OSA, CHF, and CKD. NPS was defined as NP in the absence of the other 4 etiologies. Two definitions for NP were used: NUP ≥90 mL/h and NPi ≥0.33. Male patients ≥18 years old with ≥2 nocturnal voids were included. At both NUP ≥90 mL/h and NPi ≥0.33, patients with NPS exhibited a surge in DR during the early portion of sleep (increased ENDR), followed by a drop in LNDR. A similar pattern was observed for patients with DI at NUP ≥90 mL/h. At both NUP ≥90 mL/h and NPi ≥0.33, patients with CHF, CKD, and OSA showed a gradual increase in DR from the early nocturnal to the late nocturnal period (Fig. 2). Patients with NPS and DI shared a profile of early nocturnal surge in DR followed by a decrease in the latter portion of sleep. However, patients with NP of cardiogenic and renal etiology showed a different pattern.

      Epstein M, Monaghan T, Michelson K, et al. Nocturnal diuresis rate patterns in nocturnal polyuria syndrome and secondary nocturnal polyuria. Paper presented at: Annual Meeting of the American Urological Association. May 3-6, 2019; Chicago, IL.

      Figure 2
      Figure 2Circadian pattern of diuresis rates by nocturnal polyuria etiology. DDR, diurnal diuresis rate; ENDR, early nocturnal diuresis rate; LNDR, late nocturnal diuresis rate. Reproduced with permission from Epstein et al.

      Epstein M, Monaghan T, Michelson K, et al. Nocturnal diuresis rate patterns in nocturnal polyuria syndrome and secondary nocturnal polyuria. Paper presented at: Annual Meeting of the American Urological Association. May 3-6, 2019; Chicago, IL.

      It has been suggested that there is a potential for division of NP phenotypes as per the pathophysiological mechanism pertinent to water, sodium, or mixed diuresis and more specifically increased nocturnal solute diuresis, decreased nocturnal free water reabsorption and nocturnal mixed diuresis.
      • Herek JI
      • FitzGerald MP
      • Mohindra M
      • et al.
      Solute and water excretion patterns in patients with nocturnal polyuria.
      Adults without NP have shown similar patterns for DR and solute, sodium and urea clearance, with a stable level throughout the day followed by a nocturnal decrease. In patients with NP, water diuresis is characterized by high free water clearance and low osmolality during night; solute diuresis is characterized by increased sodium clearance during night.
      • Goessaert A-S
      • Krott L
      • Hoebeke P
      • Vande Walle J
      • Everaert K
      Diagnosing the pathophysiologic mechanisms of nocturnal polyuria.
      Nocturia interventions may vary as per the different underlying mechanisms in the various etiologies of NP. Studies focused on the mechanisms specific to different etiologies will promote development of optimal management strategies for the distinct clinical entities of NP.

      Improvement of Nocturia in Patients With Reduced Bladder Capacity

      As diminished bladder capacity is one of the potential causes or associated risk factors for nocturia,
      • Weiss JP
      • Blaivas JG
      • Bliwise DL
      • et al.
      The evaluation and treatment of nocturia: a consensus statement.
      it is important to identify more effective treatment strategies for reduced bladder capacity. Current management may include: lifestyle modifications such as fluid intake restriction; medicinal treatment with α-adrenergic antagonists, antimuscarinics, or β3-adrenergic agonists; or invasive interventions such as transurethral prostate resection, neuromodulation, and botulinum toxin detrusor muscle injections.
      • Epstein MR
      • Monaghan T
      • Weiss JP
      Etiology of nocturia response in men with diminished bladder capacity.
      • Leron E
      • Weintraub AY
      • Mastrolia SA
      • Schwarzman P
      Overactive bladder syndrome: evaluation and management.
      To determine whether patients with nocturia due to reduced bladder capacity tend to improve as a result of increased bladder capacity, voiding diaries from a Veterans Affairs urology clinic between 2008 and 2017 were retrospectively analyzed.
      • Epstein MR
      • Monaghan T
      • Weiss JP
      Etiology of nocturia response in men with diminished bladder capacity.
      Adult male patients undergoing treatment for nocturia and having completed at least 2 24-hour voiding diaries ≥1 month apart, were included and divided into 2 cohorts: responders, showing any decline in nocturia, and nonresponders, showing no change or any increase in nocturia. Patients were further subdivided into those having low global bladder capacity (maximum voided volume [MVV] <200 mL) vs low nocturnal bladder capacity (nocturnal MVV [NMVV] <200 mL and MVV ≥200 mL). A total of 40 pre- and post-treatment diaries from 27 patients, and 19 pre- and post-treatment diaries from 17 patients showed low global and low nocturnal bladder capacity, respectively.
      • Epstein MR
      • Monaghan T
      • Weiss JP
      Etiology of nocturia response in men with diminished bladder capacity.
      Nocturia responders with low global bladder capacity demonstrated a decline compared with nonresponders in 24-hour volume (−130 vs + 66 mL, P = .72), NUV (−140 vs + 75, P <.01), nocturia index (Ni; −1.1 vs + 0.2, P <.01), and nocturnal bladder capacity index (NBCi; −0.59 vs + 0.23, P <.01). Similarly, patients with low nocturnal bladder capacity showed decreased 24-hour volume (−120 vs + 75 mL, P = .11), NUV (−30 vs + 160, P = .04), Ni (−0.24 vs + 0.37, P = .055), and NBCi (−1.4 vs + 0.33, P <.01). Although 24-hour volume did not meet significance for either low global or nocturnal bladder capacity, and Ni did not meet significance in the low nocturnal bladder capacity cohort, the overall trend and poorly overlapping confidence intervals led the authors to believe that significance was not achieved because of a type II error. No significant changes were seen in MVV or NMVV for either group in either global or nocturnal bladder capacity.
      • Epstein MR
      • Monaghan T
      • Weiss JP
      Etiology of nocturia response in men with diminished bladder capacity.
      Based on these findings, patients with low bladder capacity achieve improvement in nocturia severity via 4 mechanisms: fluid restriction (decreased 24-hour urine output), decreased NUV, closer alignment of nighttime urine volume and bladder capacity (decreased nocturia index), and increased tendency for nocturia voids to occur at volumes closer to bladder capacity (decreased NBCi).
      • Epstein MR
      • Monaghan T
      • Weiss JP
      Etiology of nocturia response in men with diminished bladder capacity.
      Therefore, lowering NUP is a rational strategy to treat nocturia in patients with low bladder capacity regardless of whether patients meet the criteria for a formal diagnosis of NP.
      • Epstein MR
      • Monaghan T
      • Weiss JP
      Etiology of nocturia response in men with diminished bladder capacity.

      Association Between Hypertension and Nocturia

      It is increasingly recognized that hypertension is associated with nocturia. A systematic review that identified English articles in PubMed from 1990 to 2012, providing a comprehensive evaluation of the epidemiologic evidence associating hypertension and nocturia, reported a significant association between nocturia and hypertension in the majority of the studies analyzed.
      • Feldstein CA.
      Nocturia in arterial hypertension: a prevalent, underreported, and sometimes underestimated association.
      Additionally, hypertension was reported to be an independent risk factor for nocturia (OR 1.64) in a multiphasic health screening of 6517 individuals in Japan,
      • Yoshimura K
      • Terada N
      • Matsui Y
      • Terai A
      • Kinukawa N
      • Arai Y
      Prevalence of and risk factors for nocturia: analysis of a health screening program.
      36.8% of the participants with nocturia (≥2 nightly voids) had cardiovascular disease.
      • Yoshimura K
      • Terada N
      • Matsui Y
      • Terai A
      • Kinukawa N
      • Arai Y
      Prevalence of and risk factors for nocturia: analysis of a health screening program.
      Nocturia was recently shown to be an independent, potent determinant, yet an unrecognized symptom of uncontrolled hypertension in a study on a population of middle-aged Black men.
      • Victor RG
      • Li N
      • Mason ON
      • Lynch K
      • Rashid M
      • Elashoff R
      Abstract 090: nocturia as an unrecognized symptom of uncontrolled hypertension in middle-age Black men.
      In this study to test if uncontrolled hypertension is an independent, common, and potentially reversible determinant of nocturia, interviews were conducted and blood pressure was measured in a community setting (barbershops). As nocturia is age-dependent, younger men aged 35-49 years, in whom nocturia would be unexpected, were studied. Among 1748 men, mean age (± standard deviation) 43 ± 4 years, 45% (782 of 1748) had hypertension; of these, hypertension was controlled with drugs (barbershop blood pressure <135/85 mm Hg) in only 16% (123 of 782). Nocturia prevalence ranged from 24% (232 of 966) of normotensive men to 50% (96 of 191) of men whose hypertension was drug-treated but still uncontrolled. Using normotensive men as the reference group (blood pressure 120 ± 9/71 ± 7 mm Hg) and adjusting for all known nocturia determinants, the odds of having nocturia (>2 episodes/night vs 0-1 episodes/night) was: (1) 34% higher in men with untreated hypertension (blood pressure 143 ± 11/87 ± 10 mm Hg: adjusted OR [aOR] 1.34, 95% confidence interval [CI]: 1.04-1.71, P = .02); (2) 174% higher in men with treated but uncontrolled hypertension (blood pressure 148 ± 14/91 ± 11 mm Hg: aOR 2.74, 95% CI: 1.97-3.82, P <.001); but (3) not increased in men whose hypertension was both treated and controlled (blood pressure 123 ± 8/74 ± 7 mm Hg: aOR 1.24, 95% CI: 0.81-1.89, P = .32). Nocturia was shown to signify uncontrolled hypertension in Black, 35–49-year-old men, and it may be a side effect of antihypertensive treatment agents unless strict blood pressure control is achieved.
      • Victor RG
      • Li N
      • Mason ON
      • Lynch K
      • Rashid M
      • Elashoff R
      Abstract 090: nocturia as an unrecognized symptom of uncontrolled hypertension in middle-age Black men.
      A pilot study (NCT03319823) is underway as a precursor to a study determining if using long-acting drugs and dosing them at bedtime, rather than in the morning, will lower systolic blood pressure during sleep, improve nocturia and result in better sleep quality.
      Treating Nocturnal Hypertension and Nocturia in African American men.
      It is possible that hypertension may be associated with nocturia through its effects on glomerular filtration and tubular transport,
      • Feldstein CA.
      Nocturia in arterial hypertension: a prevalent, underreported, and sometimes underestimated association.
      or indirectly through a mechanism that has yet to be identified. As we are aware, no direct causality between hypertension and nocturia has been established, and some speculate that nocturia and hypertension may have a bidirectional causal relationship.
      Patients with CKD are characterized by a less than expected decrease in blood pressure during their sleep (nondipping), and nocturia is commonly seen among these patients.
      • Agarwal R
      • Light RP
      • Bills JE
      • Hummel LA
      Nocturia, nocturnal activity, and nondipping.
      This association was studied in 98 patients with CKD,
      • Agarwal R
      • Light RP
      • Bills JE
      • Hummel LA
      Nocturia, nocturnal activity, and nondipping.
      showing that wake blood pressure levels between patients with and without nocturia were similar, but blood pressure levels during sleep were lower in patients without nocturia than those with nocturia. The average fall in systolic blood pressure was 9.8 mm Hg (95% CI: 8.0-11.6 mm Hg) in patients without nocturia, whereas the average decrease in sleep systolic blood pressure in those with nocturia was 3.4 mm Hg (95% CI: 2.7-4.1 mm Hg, P <.001 vs those without nocturia).
      • Agarwal R
      • Light RP
      • Bills JE
      • Hummel LA
      Nocturia, nocturnal activity, and nondipping.
      Additionally, a greater nighttime physical activity (measured via actigraphy [Actiwatch 64, Mini Mitter], a watch-sized device worn on the dominant wrist for the duration of ambulatory BP monitoring) than wake-time activity was observed in patients with nocturia, which in this study (patients with CKD) may have been associated with impaired renal tubular function. The increased nighttime physical activity in patients with nocturia appeared to mediate the nondipping phenomenon. The latter did not seem to be due to differences in estimated glomerular filtration rate (GFR), albuminuria, or the use of diuretics.
      • Agarwal R
      • Light RP
      • Bills JE
      • Hummel LA
      Nocturia, nocturnal activity, and nondipping.
      As lower nighttime blood pressure might account for lower GFR and less NUP, it is tempting to hypothesize that the lack of a nighttime fall in blood pressure could serve to enhance GFR and cause NP. The classic concept of renal autoregulation
      • Carlstrom M
      • Wilcox CS
      • Arendshorst WJ
      Renal autoregulation in health and disease.
      would suggest that other mechanisms are operative as GFR is maintained along a wide mean arterial pressure range (80-180 mm Hg).
      Chlorthalidone (CTD) and hydrochlorothiazide (HCTZ) are diuretic agents used in nocturnal hypertension that have been shown to inhibit the Na/Cl cotransporter in the distal convoluted renal tubule.
      • Roush GC
      • Sica DA.
      Diuretics for hypertension: a review and update.
      However, in patients with hypertension, this effect dissipates within 1-2 weeks.
      • Duarte JD
      • Cooper-DeHoff RM.
      Mechanisms for blood pressure lowering and metabolic effects of thiazide and thiazide-like diuretics.
      • Shah S
      • Khatri I
      • Freis ED
      Mechanism of antihypertensive effect of thiazide diuretics.
      With daily dosing of either CTD or HCTZ, the sustained blood pressure reduction is mediated by peripheral vasodilation via both endothelium-dependent and -independent mechanisms.
      • Duarte JD
      • Cooper-DeHoff RM.
      Mechanisms for blood pressure lowering and metabolic effects of thiazide and thiazide-like diuretics.
      Comparative studies on the antihypertensive effects of HCTZ and CTD have shown CTD to create a nocturnal dip in blood pressure as opposed to HCTZ.
      • Ernst ME
      • Carter BL
      • Goerdt CJ
      • et al.
      Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure.
      This suggests the need for future research to determine whether CTD may be a better choice than HCTZ in addressing nocturia related to the nondipping blood pressure mechanism.

      Association Between Coronary Heart Disease and Nocturia

      Nocturia has been associated with a variety of systemic disorders, including cardiovascular disease,
      • Lightner DJ
      • Krambeck AE
      • Jacobson DJ
      • et al.
      Nocturia is associated with an increased risk of coronary heart disease and death.
      • Coyne KS
      • Zhou Z
      • Bhattacharyya SK
      • Thompson CL
      • Dhawan R
      • Versi E
      The prevalence of nocturia and its effect on health-related quality of life and sleep in a community sample in the USA.
      • Bursztyn M
      • Jacob J
      • Stessman J
      Usefulness of nocturia as a mortality risk factor for coronary heart disease among persons born in 1920 or 1921.
      but it is challenging to determine whether nocturia is an early manifestation of these conditions, or a resulting complication. Thus, mechanisms underlying associations between cardiovascular disease and nocturia remain to be further elucidated.
      In a case control study with prevalence sampling, factors associated with nocturia (defined as ≥2 voids per night) were investigated in randomly identified subjects from the Finnish Population Register.
      • Tikkinen KA
      • Auvinen A
      • Johnson TM
      • et al.
      A systematic evaluation of factors associated with nocturia—the population-based FINNO study.
      Questionnaires were sent to 6000 subjects (aged 18-79 years), of which 62.4% participated (53.7% were female). Coronary artery disease was found to be associated with nocturia in the age-adjusted analyses for both sexes and in multivariate analysis for women only
      • Tikkinen KA
      • Auvinen A
      • Johnson TM
      • et al.
      A systematic evaluation of factors associated with nocturia—the population-based FINNO study.
      ; however, the association with nocturia was not present in more than half of the affected subjects of either sex.
      • Tikkinen KA
      • Auvinen A
      • Johnson TM
      • et al.
      A systematic evaluation of factors associated with nocturia—the population-based FINNO study.
      Similarly, the association between nocturia and the development of diabetes mellitus, hypertension, coronary heart disease (CHD), and death, was investigated in a retrospective cohort of 2447 randomly-selected men, aged 40-79 years followed for a median of 17.1 years.
      • Lightner DJ
      • Krambeck AE
      • Jacobson DJ
      • et al.
      Nocturia is associated with an increased risk of coronary heart disease and death.
      It was found that men younger than 60 years old with moderate nocturia (≥2 nightly voids) were more likely to develop CHD later in life than younger men without nocturia (hazard ratio [HR] 1.68, 95% CI: 1.13-2.49). However, this relationship was attenuated when adjusted for age, body mass index (BMI), and urological medications (adjusted HR 1.36, 95% CI: 0.87-2.22). Men ≥60 years old with moderate nocturia remained at increased risk of death even after adjusting for age, BMI, urological medications, and CHD (HR 1.48, 95% CI: 1.15-1.91).
      • Lightner DJ
      • Krambeck AE
      • Jacobson DJ
      • et al.
      Nocturia is associated with an increased risk of coronary heart disease and death.
      The authors suggested that nocturia may signify later development of CHD; thus, further research is needed to assess the association of nocturia with specific types of CHD.
      • Lightner DJ
      • Krambeck AE
      • Jacobson DJ
      • et al.
      Nocturia is associated with an increased risk of coronary heart disease and death.

      Association Between Arteriopathy and Nocturia

      Arterial stiffness is thought to be a key component in the development of cardiovascular disease.
      • Laurent S
      • Cockcroft J
      • Van Bortel L
      • et al.
      Expert consensus document on arterial stiffness: methodological issues and clinical applications.
      In particular, aortic stiffness is a biophysical property that reflects anatomic alterations of the arterial wall and may also reflect parallel lesions in the coronary arteries. Aortic stiffening, linked with age and other cardiovascular risk factors, is caused by breaks in elastin fibers, accumulation of collagen, fibrosis, inflammation, medial smooth muscle necrosis, calcifications, and diffusion of macromolecules within the arterial wall.
      • Laurent S
      • Cockcroft J
      • Van Bortel L
      • et al.
      Expert consensus document on arterial stiffness: methodological issues and clinical applications.
      Increase in arterial stiffness, measured by carotid-femoral pulse wave velocity (PWV), leads to a premature return of reflected waves in the late systole to the central aorta, increasing central pulse pressure and subsequently systolic blood pressure.
      • Laurent S
      • Cockcroft J
      • Van Bortel L
      • et al.
      Expert consensus document on arterial stiffness: methodological issues and clinical applications.
      The main goal of antihypertensive treatment is reduction of blood pressure
      • Agabiti-Rosei E
      • Mancia G
      • O'Rourke MF
      • et al.
      Central blood pressure measurements and antihypertensive therapy.
      and brachial blood pressure has been used as a gold-standard measure of the efficacy of antihypertensive drugs. However, blood pressure varies throughout the arterial tree due to regional differences in vessel stiffness and the influence of wave reflections. As major organs are exposed to the pressure in the central arteries rather than the peripheral arteries, central pressure is thought to be a more robust determinant of risk than brachial pressure. Antihypertensive agents exert differential effects on central pressure vs peripheral pressure and because of their differential effects on vessel stiffness and contribution of reflected pressure waves to the systolic portion of the aortic pressure waveform.
      • McEniery CM
      Antihypertensive drugs and central blood pressure.
      For example, various β-blockers may be less effective in decreasing central pressure because they do not reduce aortic stiffness and they have an adverse effect on wave reflection.
      • McEniery CM
      Antihypertensive drugs and central blood pressure.
      The notion that different antihypertensive agents (angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, β-blockers, calcium channel blockers, diuretics, and nitrates) alter vessel stiffness to variable degrees
      • McEniery CM
      Antihypertensive drugs and central blood pressure.
      underscores the importance of understanding blood pressure as a biomarker for arterial injury.
      Two studies have shown that the presence and severity of nocturia are independently associated with arterial stiffness. The relationship between nocturia and central hemodynamic parameters including central blood pressure, PWV (as a direct measure of arterial stiffness), and augmentation index (an indirect measure of arterial stiffness
      • Laurent S
      • Cockcroft J
      • Van Bortel L
      • et al.
      Expert consensus document on arterial stiffness: methodological issues and clinical applications.
      ) was investigated in patients with T2DM.
      • Afsar B
      • Elsurer R
      Central hemodynamics, vascular stiffness, and nocturia in patients with type 2 diabetes.
      A total of 302 patients were studied; of these, 158 (52.3%) had T2DM and 144 (47.7%) did not (control group). The prevalence of nocturia was higher in patients with T2DM than without T2DM; 104 (70.3%) with T2DM had nocturia (≥2 nightly voids) vs 44 (30.6%) without T2DM (P <.0001).
      • Afsar B
      • Elsurer R
      Central hemodynamics, vascular stiffness, and nocturia in patients with type 2 diabetes.
      The presence of T2DM, level of creatinine clearance, central systolic blood pressure (24 hours), and PWV (24 hours) was associated with nocturia frequency (linear regression analysis), and the presence of nocturia was associated with the presence of T2DM, creatinine clearance, age, and central diastolic blood pressure (24 hours) (logistic regression analysis). In patients with T2DM, age, creatinine clearance, and augmentation index (24 hours) were independently associated with nocturia frequency (linear regression analysis), and nocturia was associated with 24-hour creatinine clearance, hemoglobin, fasting blood glucose, and PWV (24 hours) (logistic regression analysis).
      • Afsar B
      • Elsurer R
      Central hemodynamics, vascular stiffness, and nocturia in patients with type 2 diabetes.
      Hemodynamic parameters were seen to differ between patients with and without nocturia, and in patients with T2DM, nocturia was associated with central hemodynamic and arterial stiffness parameters including PWV and augmentation index.
      • Afsar B
      • Elsurer R
      Central hemodynamics, vascular stiffness, and nocturia in patients with type 2 diabetes.
      Therefore, nocturia appears to reflect vascular injury resulting in increased arterial stiffness as well as hyperglycemia in patients with T2DM. These findings are supported by another study of 303 Japanese men with late-onset hypogonadism, in which nocturia was found to be associated with a higher brachial-ankle PWV on a multivariate linear regression model after adjustment for serum triglycerides, fasting blood sugar, and total testosterone.
      • Tsujimura A
      • Hiramatsu I
      • Aoki Y
      • et al.
      Atherosclerosis is associated with erectile function and lower urinary tract symptoms, especially nocturia, in middle-aged men.
      As PWV is an indicator of arterial stiffness,
      • Laurent S
      • Cockcroft J
      • Van Bortel L
      • et al.
      Expert consensus document on arterial stiffness: methodological issues and clinical applications.
      these results also support a relationship between nocturia and arteriopathy.
      • Tsujimura A
      • Hiramatsu I
      • Aoki Y
      • et al.
      Atherosclerosis is associated with erectile function and lower urinary tract symptoms, especially nocturia, in middle-aged men.

      BNP Levels and Nocturia—Proposed Mechanisms

      BNP levels are generally considered as a marker for heart failure.
      • Damgaard M
      • Goetze JP
      • Norsk P
      • Gadsbøll N
      Altered sodium intake affects plasma concentrations of BNP but not proBNP in healthy individuals and patients with compensated heart failure.
      It has been suggested that elevated BNP levels are associated with increased NUV.
      • Sone A
      • Kondo N
      • Kobayashi T
      • et al.
      Association with relative nocturnal polyuria using bnp (brain natriuretic peptide) in eldely patients with nocturia.
      BNP is known to be secreted from the atria of the healthy heart and from the ventricles of the failing heart as a response to cardiac wall stress.
      • Damgaard M
      • Goetze JP
      • Norsk P
      • Gadsbøll N
      Altered sodium intake affects plasma concentrations of BNP but not proBNP in healthy individuals and patients with compensated heart failure.
      • Goetze JP.
      Biochemistry of pro-B-type natriuretic peptide-derived peptides: the endocrine heart revisited.
      BNP potentiates diuresis, elicits vasodilation, and antagonizes the function of the renin-angiotensin-aldosterone system to maintain cardiorenal homeostasis.
      • Fu S
      • Ping P
      • Zhu Q
      • Ye P
      • Luo L
      Brain natriuretic peptide and its biochemical, analytical, and clinical issues in heart failure: a narrative review.
      • Semenov AG
      • Katrukha AG.
      Different susceptibility of B-type natriuretic peptide (BNP) and BNP precursor (proBNP) to cleavage by neprilysin: The N-terminal part does matter.
      BNP levels in 128 patients treated for nocturia were examined in patients who completed voiding diaries for 4 days, while they continued their urologic treatments (α-blockers or anticholinergic agents).
      • Sone A
      • Kondo N
      • Kobayashi T
      • et al.
      Association with relative nocturnal polyuria using bnp (brain natriuretic peptide) in eldely patients with nocturia.
      A close relationship between BNP levels and the 24-hour urine volume (P = .0215), the daytime urine volume (P = .0004), and the NPi (P = .0003) was observed. The daytime urine volume was seen to decrease with the BNP level, and the NPi increased with the BNP level. In patients with a BNP level less than 50 pg/mL, the NUV rate was 38.14 ± 10.07%. In patients with a BNP level of 50 pg/mL or more, the NUV rate was significantly higher (43.97 ± 10.48%, P <.0029). Thus, in patients with mild heart failure, relative NP may reduce cardiac load. Since BNP levels reflect sodium and water overload, the authors suggested that antidiuretic hormone acting agents could lead to further volume overload and decompensation.
      • Sone A
      • Kondo N
      • Kobayashi T
      • et al.
      Association with relative nocturnal polyuria using bnp (brain natriuretic peptide) in eldely patients with nocturia.
      In addition, in a study investigating the influence of cardiac load evaluated by BNP on nocturia, BNP was shown to be an independent risk factor of nocturia with a median BNP in men with nocturia of 26.5 pg/mL vs 13.7 pg/mL (P <.01) in those without nocturia.
      • Izumi K
      • Ito M
      • Inoue M
      Impact of brain-type natriuretic peptide, a representative biomarker for cardiac load, on nocturia in men.
      Elevated BNP levels are considered as evidence of intravascular volume overload. Plasma BNP levels have been shown to increase in response to moderate physiological increase in sodium intake, probably due to central blood volume expansion.
      • Damgaard M
      • Goetze JP
      • Norsk P
      • Gadsbøll N
      Altered sodium intake affects plasma concentrations of BNP but not proBNP in healthy individuals and patients with compensated heart failure.
      Elevated levels of BNP may also be predictive of nocturia as they are proposed to contribute to nocturia by enhancing natriuresis. Additionally, BNP levels are significantly greater in patients with impaired left ventricular function than in those with normal heart function. However, data relating BNP levels and nocturia have not been consistent with some showing similar BNP levels among patients with and without NP. Disparate results may be related to differences in patient populations studied with varying frequencies of volume overload and comorbid conditions. Whether increased BNP levels mechanistically underpin nocturia or are a marker of subclinical volume overload merits further study.
      • Torimoto K
      • Hirayama A
      • Samma S
      • Yoshida K
      • Fujimoto K
      • Hirao Y
      The relationship between nocturnal polyuria and the distribution of body fluid: assessment by bioelectric impedance analysis.
      • Hirayama A
      • Fujimoto K
      • Akiyama T
      • Hirao Y
      Decrease in nocturnal urinary levels of arginine vasopressin in patients with nocturnal polyuria.

      Distribution of Body Fluid and Relationship With NP

      Evacuation of daytime third-space fluid sequestration with peripheral edema due to a recumbent position for sleep is one of the factors from which overproduction of urine at night may result.
      • Weiss JP.
      Nocturia: focus on etiology and consequences.
      In particular, it has been suggested that, in patients with NP, surplus water accumulates in segments of the body throughout the day, which is then excreted as urine during the night.
      • Torimoto K
      • Hirayama A
      • Samma S
      • Yoshida K
      • Fujimoto K
      • Hirao Y
      The relationship between nocturnal polyuria and the distribution of body fluid: assessment by bioelectric impedance analysis.
      The relationship between NP and the variation of body fluid distribution during daytime was explored via bioelectric impedance analysis
      • Torimoto K
      • Hirayama A
      • Samma S
      • Yoshida K
      • Fujimoto K
      • Hirao Y
      The relationship between nocturnal polyuria and the distribution of body fluid: assessment by bioelectric impedance analysis.
      in 34 men older than 60 years of age. NP was defined as an NUV per 24-hour production of greater than 0.35 (NPi) and bioelectric impedance analysis was performed 4 times daily.
      • Torimoto K
      • Hirayama A
      • Samma S
      • Yoshida K
      • Fujimoto K
      • Hirao Y
      The relationship between nocturnal polyuria and the distribution of body fluid: assessment by bioelectric impedance analysis.
      The increase in extracellular fluid compared with the volume at 8 AM was significantly larger at 9 PM in patients with NP vs those without NP; however, intracellular fluid volumes were not significantly different between the groups at any time.
      • Torimoto K
      • Hirayama A
      • Samma S
      • Yoshida K
      • Fujimoto K
      • Hirao Y
      The relationship between nocturnal polyuria and the distribution of body fluid: assessment by bioelectric impedance analysis.
      More extracellular fluid accumulated in the legs, suggesting water accumulation in the form of edema in the interstitial space of the legs in the evening in patients with NP, compared with those without NP. The volume of accumulated water in the legs was associated with NUV, suggesting that extra water was not excreted as urine during the day, but rather accumulated in the legs due to gravity and was excreted as urine during the night when the patients were in a recumbent position.
      • Torimoto K
      • Hirayama A
      • Samma S
      • Yoshida K
      • Fujimoto K
      • Hirao Y
      The relationship between nocturnal polyuria and the distribution of body fluid: assessment by bioelectric impedance analysis.
      The authors suggested that leg edema is the source of nocturnal urine and that by decreasing edema, NP may improve. The authors further proposed that prevention of third-spacing during the day, in patients with nocturia due to NP, could be achieved via evening exercise, compressive lower extremity stockings and salt avoidance.
      • Torimoto K
      • Hirayama A
      • Samma S
      • Yoshida K
      • Fujimoto K
      • Hirao Y
      The relationship between nocturnal polyuria and the distribution of body fluid: assessment by bioelectric impedance analysis.

      Daily Salt Intake as a Risk Factor for Pollakiuria and Nocturia

      There are several studies on the relationship between salt intake and LUTS; however, accumulated evidence had not demonstrated a significant relationship between nocturia and salt intake.
      • Matsuo T
      • Miyata Y
      • Sakai H
      Daily salt intake is an independent risk factor for pollakiuria and nocturia.
      • Hendi K
      • Leshem M.
      Salt appetite in the elderly.
      • Yoshimura K
      • Terai A.
      Fluctuation of night time frequency in patients with symptomatic nocturia.
      Physiological reactions to excessive salt intake may result in pollakiuria, and increased water intake due to salt-induced increases in serum osmolality leading to pollakiuria, which is induced by polyuria, suggesting that salt intake is associated with increased urinary frequency.
      • Matsuo T
      • Miyata Y
      • Sakai H
      Daily salt intake is an independent risk factor for pollakiuria and nocturia.
      To clarify the association between salt intake and LUTS, including nocturia, urine samples were collected from 728 patients with LUTS and daily salt intake was estimated. Patients were divided into 2 groups based on the median salt intake (9.2 g/day). Urinary conditions were evaluated using the Core LUTS score and 3-day voiding diaries.
      • Matsuo T
      • Miyata Y
      • Sakai H
      Daily salt intake is an independent risk factor for pollakiuria and nocturia.
      Results showed that in the high salt group, daytime and nighttime urinary frequency, diurnal and NUV, as well as NPi were significantly higher than in the low salt group (Table 1). Additionally, on correlation analysis, estimated daily salt intake was positively associated with daytime and nighttime urinary frequency, diurnal and NUV, and NPi. On multivariate analysis, higher salt intake and hypertension were found to be significant and independent predictors for daytime urinary frequency. Daily salt intake, old age, male sex, high BMI, renal dysfunction, and hypertension were significantly associated with high frequency of nocturnal urination. High salt intake was shown to be a significant and independent aggravating factor for nocturia (multivariate analysis: OR 3.05, 95% CI: 2.08-4.52, P <.001).
      • Matsuo T
      • Miyata Y
      • Sakai H
      Daily salt intake is an independent risk factor for pollakiuria and nocturia.
      It was proposed that NPi was higher in the high salt group in this study because excessive salt intake may increase permeability, leading to peripheral edema in the interstitium at the capillary level, and peripheral edema has been suggested to be associated with NUV and NPi.
      • Torimoto K
      • Hirayama A
      • Samma S
      • Yoshida K
      • Fujimoto K
      • Hirao Y
      The relationship between nocturnal polyuria and the distribution of body fluid: assessment by bioelectric impedance analysis.
      • Matsuo T
      • Miyata Y
      • Sakai H
      Daily salt intake is an independent risk factor for pollakiuria and nocturia.
      • Hirayama A
      • Torimoto K
      • Yamada A
      • et al.
      Relationship between nocturnal urine volume, leg edema, and urinary antidiuretic hormone in older men.
      It has been observed that increased water intake following excessive salt intake during the daytime results in elevated circulating blood volume and subsequent stimulation of atrial natriuretic peptide and BNP due to the volume overload. Therefore, elevated levels of atrial natriuretic peptide and BNP may further result in nocturnal diuresis and NP.
      • Matsuo T
      • Miyata Y
      • Sakai H
      Daily salt intake is an independent risk factor for pollakiuria and nocturia.
      • Fujikawa K
      • Kasahara M
      • Matsui Y
      • Takeuchi H
      Human atrial natriuretic peptide is a useful criterion in treatment of nocturia.
      The authors suggested that an appropriate control of salt intake and blood pressure may be important for the treatment of pollakiuria and nocturia.
      Table 1Urinary conditions in participants with lower urinary tract symptoms, including nocturia, based on salt intake
      Urinary ConditionHigh Salt GroupLow Salt GroupP Value
      Daytime urinary frequency8.4 ± 2.46.9 ± 2.5P <.001
      Nighttime urinary frequency2.2 ± 1.31.4 ± 1.3P <.001
      Diurnal urine volume1811.7 ± 477.7 mL1590 ± 502.3 mLP <.001
      NUV517.7 ± 241.1 mL153.7 ± 146.8 mLP <.001
      NPi21.7 ± 7.9%8.1 ± 7.4%P <.001
      NPi, nocturnal polyuria index; NUV, nocturnal urine volume.
      Adapted with permission from Matsuo et al.
      • Matsuo T
      • Miyata Y
      • Sakai H
      Daily salt intake is an independent risk factor for pollakiuria and nocturia.

      Conclusions and Future Lines of Investigation

      Patients diagnosed with NPS showed a distinct rate of urine production throughout the night, marked by a drop-off in nocturnal DR after the time of first awakening, a pattern unique to patients with NPS. The NPS phenotype remains to be further characterized to identify those patients who are most likely to benefit from short-acting antidiuretic replacement therapy. The exact role of antidiuretics in altering the nocturnal DR in patients with NPS is to be further investigated.
      • Monaghan TF
      • Suss NR
      • Epstein MR
      • et al.
      Differential nocturnal diuresis rates among patients with and without nocturnal polyuria syndrome.
      Nocturia due to reduced global bladder capacity was seen to improve by decreasing NUV, possibly via both reduced fluid intake and nocturnal voiding at volumes closer to capacity. Changes in bladder capacity had no effect in driving the improvement in nocturia that was observed. Currently, there are no pharmaceutical agents that significantly increase bladder capacity; thus, treatment directed at lowering NUP and enabling patients to void at capacity is a rational strategy for nocturia treatment in patients with low bladder capacity.
      • Epstein MR
      • Monaghan T
      • Weiss JP
      Etiology of nocturia response in men with diminished bladder capacity.
      The association between nocturia and hypertension is supported by epidemiologic evidence and it is, therefore, important that primary care physicians proactively ask patients with hypertension about nocturnal voiding.
      • Feldstein CA.
      Nocturia in arterial hypertension: a prevalent, underreported, and sometimes underestimated association.
      Furthermore, nocturia was shown to signify uncontrolled hypertension, being more likely to occur when hypertension was inadequately treated than when untreated, suggesting that nocturia may be a side-effect of antihypertensive treatment unless strict blood pressure control is achieved.
      • Victor RG
      • Li N
      • Mason ON
      • Lynch K
      • Rashid M
      • Elashoff R
      Abstract 090: nocturia as an unrecognized symptom of uncontrolled hypertension in middle-age Black men.
      In addition to hypertension, excessive daily salt intake was shown to be a significant and independent risk factor for nocturia.
      • Matsuo T
      • Miyata Y
      • Sakai H
      Daily salt intake is an independent risk factor for pollakiuria and nocturia.
      Thus, sodium restriction may carry the potential to be an effective adjunct therapy to other treatments such as short-acting antidiuretics, including desmopressin, in patients without obvious heart failure or uncontrolled hypertension.
      As nocturia has been shown to reflect vascular damage in the form of arterial stiffness, it remains to be investigated whether treatment to reduce arterial stiffness could reduce nocturia or whether appropriate antihypertensive treatment could ameliorate nocturia as a symptom. Studies have shown nocturia to be associated with PWV in patients with T2DM and late-onset hypogonadism
      • Afsar B
      • Elsurer R
      Central hemodynamics, vascular stiffness, and nocturia in patients with type 2 diabetes.
      • Tsujimura A
      • Hiramatsu I
      • Aoki Y
      • et al.
      Atherosclerosis is associated with erectile function and lower urinary tract symptoms, especially nocturia, in middle-aged men.
      ; however, additional research is necessary to establish a connection between nocturia and subclinical markers of vascular disease. Similarly, the possibility of a connection between diminished bladder capacity and vascular dysfunction remains to be explored.
      Despite studies showing that excessive salt intake is a risk factor for nocturia, whether there is a complementary or even synergistic relationship between sodium restriction and antidiuretic therapy warrants further investigation. In addition, a definitive link between sodium vs free water diuresis NP phenotype and differential DRs has not yet been established.
      Nocturia was seen to correlate with nondipping blood pressure in patients with CKD; however, further research is necessary to determine the nature of this relationship. Nocturia and nondipping blood pressure could either be directly related via a mechanism that is yet to be identified, or they could be coexisting manifestations of volume overload. Furthermore, BNP is implicated in diuresis, natriuresis, and vasodilation and is used as a marker for heart failure, while increased levels of BNP are evidence of intravascular volume overload. It has been suggested that elevated BNP levels may be predictive of nocturia; however, whether BNP levels could be part of the therapeutic construct for nocturia is another area of pending investigation.
      As there are multiple physiological mechanisms and subsequent chronic conditions associated with nocturia and NP, such as high blood pressure, cardiovascular disease, T2DM, and other metabolic disorders, a multispecialty approach to diagnosis and management is essential to improve treatment outcomes in these patients. For instance, voiding diaries could be utilized in nonurological practices and sodium intake questionnaires could be used in urological practices along with referral for vascular screening. To this end, an interdisciplinary collaboration between urologists and cardiologists would be beneficial to further investigate the mechanisms underlying nocturia and NP and to optimize patient-oriented treatment approaches.

      Acknowledgments

      The authors gratefully acknowledge the contributions of the following individuals who participated in discussion that shaped the content of this article: Lori A Birder; Donald L Bliwise; Karel Everaert; Peter K Sand; Philip EV Van Kerrebroeck; and Adrian Wagg. Writing and editorial assistance were provided by Diane Kwiatkoski, Sharon Suntag, Chrysi Petraki, and Eric Weathers of IQVIA.

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